NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23 of PTCH1. SpliceAI predicts no splicing impact (max delta 0.00) and REVEL score is 0.27 in the neutral range, consistent with no functional effect.1 The variant is present at very low frequency in population databases: 10/282,784 alleles in gnomAD v2.1 (AF=0.0035%) and 50/1,614,202 alleles in gnomAD v4.1 (AF=0.0031%), with no homozygotes observed.2 ClinVar classifies this variant as Likely benign, supported by 5 independent clinical testing laboratories. No reputable source reports this variant as pathogenic.3 Seven publications were reviewed for variant-specific evidence, including the ACMG/AMP 2015 guidelines (PMID:25741868), Sherloc refinement (PMID:28492532), GeneReviews NBCCS overview (PMID:20301330), and Gorlin syndrome clinical utility gene card (PMID:21304560). None mention NM_000264.5:c.4251C>T specifically.4 Application of ACMG/AMP 2015 generic combination rules: three supporting benign criteria (BP4, BP6, BP7) and one supporting pathogenic criterion (PM2) are met. The preponderance of evidence supports a Likely benign classification.5
PTCH1
Final classification
Likely Benign
PTCH1 c.4251C>T · p.His1417=
PTCH1
NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23 of PTCH1. SpliceAI predicts no splicing impact (max delta 0.00) and REVEL score is 0.27 in the neutral range, consistent with no functional effect.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6BP7
Likely Benign
PTCH1 c.4251C>T
PM2 + BP4 + BP6 + BP7
→
Likely Benign
1
spliceai ↗revel
4
PMID:25741868 ↗PMID:28492532 ↗PMID:20301330 ↗PMID:21304560 ↗PMID:15604628 ↗PMID:26389258 ↗PMID:26389333 ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_000264.5 · variants mapped to exon structure
PTCH1
NM_000264.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 16 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000264.5:c.4251C>T is present at extremely low frequency in population databases, below the 0.1% PM2 threshold for non-VCEP generic ACMG. gnomAD v2.1: 10/282,784 alleles (AF=0.0035%); gnomAD v4.1: 50/1,614,202 alleles (AF=0.0031%); gnomAD-Canada: 0 alleles. No homozygotes observed.
gnomAD v2.1 AF=0.00354% (10/282784 alleles)gnomAD v4.1 AF=0.00310% (50/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.27, in the neutral range. The variant is synonymous (p.His1417=) with no predicted effect on splicing or protein function.
SpliceAI max delta: 0.00 (no splicing impact)REVEL score: 0.27 (neutral range)Synonymous variant with no predicted functional consequence
✓
BP6
supporting
Benign
ClinVar classifies NM_000264.5:c.4251C>T as Likely benign, supported by 5 clinical laboratories (Ambry Genetics, Invitae/Labcorp, Copenhagen University Hospital, PreventionGenetics, CeGaT). Multiple reputable clinical testing laboratories have independently reached a benign interpretation.
ClinVar: Likely benign5 clinical laboratories (ClinVar ID 132735)Submitting labs: Ambry Genetics
✓
BP7
supporting
Benign
NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23. SpliceAI predicts no splicing impact (max delta 0.00). The nucleotide is not located at a highly conserved position predicted to affect splicing. BP7 is met for a synonymous variant with no predicted splice effect.
Synonymous variant p.His1417=SpliceAI max delta: 0.00 (no splicing impact predicted)No evidence of altered splicing
Assessed · not applied
Pathogenic
PS2
No de novo data are available for NM_000264.5:c.4251C>T.
PS3
No variant-specific functional studies were identified for NM_000264.5:c.4251C>T.
PS4
No variant-specific case-control or cohort prevalence data were identified.
PM1
Residue p.His1417 is not located in a statistically significant mutational hotspot (evidence_brief confirms hotspot analysis negative).
PM6
No de novo data are available for NM_000264.5:c.4251C>T.
PP1
No co-segregation data are available for NM_000264.5:c.4251C>T.
PP3
In silico predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data were provided for assessment.
PP5
PP5 requires a reputable source to report the variant as pathogenic.
Benign
BA1
Allele frequency in gnomAD is far below the 1% BA1 threshold.
BS1
Allele frequency is below the 0.3% BS1 threshold for non-VCEP generic ACMG.
BS2
No specific evidence of observation in healthy adults beyond population database allele counts.
BS3
No variant-specific functional studies were identified for NM_000264.5:c.4251C>T demonstrating no damaging effect.
BS4
No non-segregation data are available for NM_000264.5:c.4251C>T.
BP2
No data are available on observation of NM_000264.5:c.4251C>T in trans with a known pathogenic PTCH1 variant.
BP5
No evidence of an alternate molecular basis for disease was identified in the case.
N/A · 6
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09751e-05; MAF= 0.00310%, 50/1614202 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.7287e-05; MAF= 0.00373%, 44/1180036 alleles, homozygotes = 0); grpmax FAF= 2.826e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.53627e-05; MAF= 0.00354%, 10/282784 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.46501e-05; MAF= 0.00847%, 3/35440 alleles, homozygotes = 0); grpmax FAF= 1.686e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0031%
· 50 / 1,614,202
0 hom · FAF 0.0028%
0 hom · FAF 0.0028%
European (non-Finnish) 44 / 1,180,036 |
0.0037% |
Admixed American 2 / 60,032 |
0.0033% |
African/African American 2 / 75,058 |
0.0027% |
South Asian 2 / 91,088 |
0.0022% |
+ 6 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0035%
· 10 / 282,784
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
Admixed American 3 / 35,440 |
0.0085% |
African/African American 1 / 24,956 |
0.004% |
European (non-Finnish) 5 / 129,106 |
0.0039% |
South Asian 1 / 30,616 |
0.0033% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories). (ClinVarID = 132735)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.27.
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR